IMMUNOLOGIC RESEARCH
·
2025
·Vol. 73
·期 1
·1-20
·
IF 3.1
Xu Cong,Lu Chenqi,Wang Wu,Wang Zhimin,Qiu Yang,Han Min,Yang Jun,Li Shanglin
Autoimmune hepatitis (AIH) is an immune-mediated liver disease that currently lacks viable drug treatment methods. This study is to explore the role of piceatannol (PIC) in ConA-induced AIH and the related mechanisms. A mouse model of AIH was established by injecting ConA (i.v.), and PIC was administered as an intervention. The protective effect of PIC was evaluated by the liver function, liver pathology, and serum levels of inflammatory factors. Subsequently, network pharmacology was used to predict the pathways and targets of PIC in the treatment of AIH, and the predicted results were validated using flow cytometry, molecular docking, surface plasmon resonance (SPR) and so on. Finally, the immunosuppressive effect of PIC was further validated in a mouse heart transplantation model. PIC can improve liver function decline and reduce pathological liver damage, as well as inhibit the increase of serum inflammatory factor levels in mice with AIH induced by ConA. The protective effect is achieved by suppressing the immune activity of T cells and macrophages through binding to c-Jun. PIC can also extend the survival of cardiac allografts and inhibit acute rejection reactions. These results indicated that PIC can significantly improve ConA-induced AIH in mice by inhibiting the immune activity of T cells and macrophages through binding to c-Jun. PIC can also extend the survival of cardiac allografts in mice and inhibit acute rejection responses. The above results indicated that PIC may serve as a promising immunosuppressant and be effective for AIH.
研究领域:
免疫学
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肝病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Lifeng Ding,Lili Jiang,Ze Xing,Huixu Dai,Jingzan Wei
The regulatory mechanism on granulosa cells (GCs) oxidative injury is becoming increasingly important in polycystic ovary syndrome (PCOS) studies. Serine/threonine kinase mitogen-activated protein 4 kinase 4 (Map4k4) is linked with oxidative injury and possibly associated with premature ovarian failure and ovarian dysgenesis. Herein, we investigated the function and mechanism of Map4k4 in a PCOS rat model. A microarray from GEO database identified Map4k4 was up-regulated in the ovarian of PCOS rats, and functional enrichments suggested that oxidative stress-associated changes are involved. We verified the raised Map4k4 expression in an established PCOS rat model and also in the isolated PCOS-GCs, which were consistent with the microarray data. Map4k4 knockdown in vivo contributed to regular estrous cycle, restrained steroid concentrations and ovarian injury in PCOS rats. Both Map4k4 silencing in vivo and in vitro attenuated the PCOS-related GC oxidative stress and apoptosis. Mechanically, Map4k4 activated the JNK/c-JUN signaling pathway. Importantly, a JNK agonist restored the suppressive effects of Map4k4 silencing on PCOS-induced granulosa cell injury and oxidative stress. Besides, Map4k4 may be a target gene of miR-185-5p. In conclusion, Map4k4, a potential target of miR-185-5p, is up-regulated and induces ovarian GC oxidative injury by activating JNK/c-JUN pathway in PCOS. The Map4k4/JNK/c-JUN mechanism may provide a new idea on the treatment of PCOS.
研究领域:
生殖生物学
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
MOLECULAR HUMAN REPRODUCTION
·
2014
·Vol. 20
·期 8
·799-809
·
IF 3.483
Wang Yongjie,Tang Chao,Wu Minglan,Pan Yibin,Ruan Hongfeng,Chen Linling,Yao Hongyi,Zhu Haibin,Wu Ximei
We have previously demonstrated that the reduced form of vitamin C (l-ascorbic acid, AA) is able to induce the production of both steroid and peptide hormones in human choriocarcinoma cells. Here, we attempted to investigate the role and underlying mechanism of the oxidized form of vitamin C, dehydroascorbic acid (DHA), in steroidogenesis in primary human cytotrophoblasts and human choriocarcinoma cells. Messenger RNA and protein levels of steroidogenic enzymes including P450 cholesterol side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) and aromatase were examined by quantitative RT–PCR and western blots, respectively. Progesterone (P4) and estradiol (E2) levels were determined by enzyme immunoassays. Knockdown of c-Jun was achieved by lentivirus-mediated shRNA, and signaling pathways implicated in DHA-induced steroidogenesis were examined by western blots and dual-luciferase assays. DHA dose-dependently induced the expression of steroidogenic enzymes including 3β-HSD1, 17β-HSD1 and aromatase at both mRNA and protein levels, and subsequently increased the production of E2 but not P4. These effects were synergized by diethylmaleate, a glutathione-depleting compound, and α-tocopherol, a reducing agent, but robustly attenuated by inhibition of DHA transportation by phloretin or 2-deoxy-d-glucose. DHA time-dependently inhibited JNK and c-Jun phosphorylation, and dose-dependently reduced AP1 reporter activity. JNK signaling pathway-specific inhibitor SP600125 and c-Jun shRNA both significantly increased the expression of steroidogenic enzymes and E2 production regardless of the presence or absence of DHA. These findings suggest that DHA is able to induce steroidogenesis through inhibition of JNK/c-Jun/AP1 signaling, and may therefore play indispensable roles in pregnancy maintenance.
研究领域:
内分泌学
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细胞生物学
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分子生物学
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生殖生物学
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DOI
PubMed
高影响因子
Cancer Cell International
·
2024
·
IF 5.3
Boya Deng,Siyang Zhang,Yingying Zhou,Ting Sun,Ying Zhu,Jing Fei,Ailin Li,Yuan Miao
Coiled-coil domain containing 88C (CCDC88C) is a component of non-canonical Wnt signaling, and its dysregulation causes colorectal cancer metastasis. Dysregulated expression of CCDC88C was observed in lymph node metastatic tumor tissues of breast cancer. However, the role of CCDC88C in breast cancer metastasis remains unclear. To address this, the stable BT549 and SKBR3 cell lines with CCDC88C overexpression or knockdown were developed. Loss/gain-of-function experiments suggested that CCDC88C drove breast cancer cell motility in vitro and lung and liver metastasis in vivo. We found that CCDC88C led to c-JUN-induced transcription activation. Overlapping genes were identified from the genes modulated by CCDC88C and c-JUN. CEMIP , one of these overlapping genes, has been confirmed to confer breast cancer metastasis. We found that CCDC88C regulated CEMIP mRNA levels via c-JUN and it exerted pro-metastatic capabilities in a CEMIP-dependent manner. Moreover, we identified the CCDC88C as a substrate of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6). GALNT6 was positively correlated with CCDC88C protein abundance in the normal breast and breast cancer tissues, indicating that GALNT6 might be associated with expression patterns of CCDC88C in breast cancer. Our data demonstrated that GALNT6 maintained CCDC88C stability by promoting its O-linked glycosylation, and the modification was critical for the pro-metastatic potential of CCDC88C. CCDC88C also could mediate the pro-metastatic potential of GALNT6 in breast cancer. Collectively, our findings uncover that CCDC88C may increase the risk of breast cancer metastasis and elucidate the underlying molecular mechanisms. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-024-03413-2.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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PubMed
高影响因子
PLANTA MEDICA
·
2022
·Vol. 88
·期 13
·1233-1244
·
IF 3.007
Shipeng Chen,Yinan Liao,Jinyan Lv,Huaxin Hou,Jie Feng
The aim of the present study was to investigate the cytotoxic effects and underlying molecular mechanisms of nitidine chloride (NC) in hepatocellular carcinoma cells via quantitative proteomics. MTT assays were used to detect the inhibitory effects of NC in Bel-7402 liver cancer cells, and the number of apoptotic cells was measured by flow cytometry. Quantitative proteomics technology based on iTRAQ was used to discover differential expressed proteins after NC treatment, and bioinformatic techniques were further used to screen potential targets of NC. Molecular docking was applied to evaluate the docking activity of NC with possible upstream proteins, and their expression was detected at the mRNA and protein levels by quantitative reverse transcription PCR and western blotting. NC inhibited the proliferation of Bel-7402 cells after 24 h of treatment and stimulated apoptosis in vitro. The proteomics experiment showed that NC triggers mitochondrial damage in HCC cells and transcription factor AP-1 (c-Jun) may be a potential target of NC (fold change = 4.36 ± 0.23). Molecular docking results revealed the highest docking score of NC with c-Jun N-terminal kinase (JNK), one of the upstream proteins of c-Jun. Moreover, the mRNA and protein expression of c-Jun and JNK were significantly increased after NC treatment (p
研究领域:
癌症生物学
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分子生物学
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药理学
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蛋白质组学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Qi-Rui Hu,Qing-Xin Huang,Huan Hong,Yao Pan,Ting Luo,Jing Li,Ze-Yuan Deng,Fang Chen
s Background Liver cancer is a topical global health issue. The treatment of liver cancer meets significant challenges in the high recurrence rate and invasive incidence. Therefore, the treatment strategies that target epithelial-mesenchymal transition (EMT) induced by cyclooxygenase 2 (COX2)/ prostaglandin E2 (PGE2) pathway have become epidemic. Ginsenoside Rh2 has been proved to inhibit the EMT. However, the underlying mechanisms remain unclear. Moreover, the octyl ester derivative of Rh2 (Rh2-O) exhibited superior anti-proliferative and immunomodulatory effects than Rh2 in our previous researches, which indicated that Rh2-O might also exert inhibitory effects on invasion and metastasis . Purpose The aim of current study is to explore the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis of hepatocellular carcinoma , and to investigate whether these effects are dependent on the c-Jun/COX2/PGE2 pathway. Study Design The Huh-7 liver cancer cells and the H22 tumor-bearing mice were treated with Rh2 and Rh2-O. Method In this paper, the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis were tested by wound healing, trans-well assay and tumor-bearing mice, and the involvement of c-Jun/COX2/PGE2 pathway were verified by exogenous PGE2, activation of COX2 and overexpression of c-Jun. Results The results showed that Rh2 and Rh2-O could efficiently inhibit the invasion and metastasis in a dose-dependent manner ( p < 0.05). And the Rh2-O showed stronger effects than Rh2. Moreover, the exogenous PGE2, activation of COX2 by exogenous LPS and the overexpression of c-Jun by transfection all reversed the inhibitory effects of Rh2 and Rh2-O on metastasis or EMT ( p < 0.05). Conclusion Rh2 and Rh2-O could inhibit the invasion and metastasis of hepatocellular carcinoma via restraining the EMT, which was mediated by c-Jun/COX2/PGE2 pathway.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Yi Huang,Fengling Liu,Shuhua Ren,Yuanqing Ding,Man Chi,Weiwei Huang,Wenjing Gu,Hewen Qian,Yaxia Yuan,Shurong Hou,Xiabin Chen,Lei Ma
Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease with an elusive etiology. Aberrant activation of c-Jun N-terminal kinase 1 (JNK1) has been implicated in its pathogenesis. Through a combination of structure-based drug design and structure–activity relationship (SAR) optimization, a series of pyrimidine-2,4-diamine scaffold derivatives have been developed as potent JNK1 inhibitors. Compound E1 was identified with low nanomolar JNK1 inhibitory potency (IC50 = 2.7 nM). The introduction of a dimethylamine side chain has significantly enhanced the ability of E1 to inhibit c-Jun phosphorylation, surpassing the clinical candidate CC-90001. Molecular dynamics simulations revealed a binding free energy of −50.46 kcal/mol for E1. Moreover, E1 displayed satisfactory pharmacokinetic properties, with a bioavailability of 69% in rats. Furthermore, compound E1 exerted significant antifibrotic effects in a bleomycin-induced IPF mouse model and prevented a TGF-β-induced epithelial-to-mesenchymal transition in vitro. These findings position E1 as a promising lead for further drug development targeting IPF.
研究领域:
药理学
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药物化学
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肺科学
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药物发现
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DOI
PubMed
高影响因子
EXPERIMENTAL EYE RESEARCH
·
2021
·
IF 3.467
Lei Tao,Danxue He,Chunyan Liao,Binxiang Cai,Chao Chen,Yan Wang,Jingmeng Chen,Zuguo Liu,Yalin Wu
Retinal pigment epithelium (RPE) cell apoptosis arising from all- trans -retinal (atRAL) is in close contact with the etiology of dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its underlying mechanisms remain elusive. In this study, we reported that c-Jun N -terminal kinase (JNK) activation facilitated atRAL-induced apoptosis of RPE cells. Reactive oxygen species production and endoplasmic reticulum stress were identified as two of major upstream events responsible for activating JNK signaling in atRAL-loaded RPE cells. Inhibiting JNK signaling rescued RPE cells from apoptosis induced by atRAL through attenuating caspase-3 activation leading to poly-ADP-ribose polymerase (PARP) cleavage, and DNA damage response . Abca4 −/− Rdh8 −/− mice upon light exposure exhibit rapidly increased accumulation of atRAL in the retina , and display severe RPE degeneration, a primary attribute of dry AMD and STGD1. Reducing JNK signaling by intraperitoneally injected JNK–IN-8 was highly effective in preventing RPE atrophy and apoptosis in light-exposed Abca4 −/− Rdh8 −/− mice. These findings afford a further understanding for contribution of JNK activation by atRAL to retinal damage .
研究领域:
眼科学
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分子生物学
·
细胞生物学
·
神经退行性疾病
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PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2019
·
IF 6.054
Xiaodong Dou,Huixia Huang,Yibo Li,Lan Jiang,Yanxing Wang,Hongwei Jin,Ning Jiao,Lihe Zhang,Liangren Zhang,Zhenming Liu
Alzheimer’s disease (AD) is one of the most challenging diseases around the world with no effective clinical treatment. Previous studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive therapeutic target for AD. Herein, we report 3-substituted indolin-2-one derivatives as the first isoform-selective JNK3 inhibitors by multistage screening. In this study, comparative structure-based virtual screening was performed, and J30-8 was identified with a half-maximal inhibitory concentration of 40 nM, which exhibited over 2500-fold isoform selectivity and marked kinome-wide selectivity. Further study indicated that 1 μM J30-8 exhibited neuroprotective activity in vitro so as to alleviate the spatial memory impairment in vivo through reducing plaque burden and inhibiting the phosphorylation of JNKs, Aβ precursor protein, and Tau protein. All of these indicated J30-8 as proved isoform-selective JNK3 inhibitors that might serve as a useful tool for further JNK3 studies with AD as well as for the development of JNK3 inhibitors for the potential treatment of neurodegenerative diseases.
研究领域:
神经科学
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药理学
·
药物发现
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2022
·
IF 5.895
Wan Wang,Cong Xu,Xuan Zhou,Le Zhang,Liya Gu,Zhijing Liu,Jiage Ma,Juncai Hou,Zhanmei Jiang
Probiotics and prebiotics have received attention in alleviating neurodegenerative diseases. Lactobacillus plantarum (L. plantarum) 69-2 was combined with galactooligosaccharides (GOS) and supplemented in a d-galactose (d-gal)-induced neurodegeneration and memory impairment mice model to explore its effects on the brain and the regulation of short-chain fatty acids. The results showed that the L. plantarum-GOS supplementation inhibited d-gal-induced oxidative stress and increased the brain’s nuclear factor erythroid 2-related factor 2 (Nrf2) levels. Butyrate, a metabolite of the gut microbiota regulated by L. plantarum combined with GOS, inhibits p-JNK expression, downregulates pro-apoptotic proteins expression and the activation of inflammatory mediators, and upregulates synaptic protein expression. This might be a potential mechanism for L. plantarum 69-2 combined with GOS supplementation to alleviate d-gal-induced neurodegeneration and memory impairment. This study sheds new light on the development of aging-related neuroprotective dietary supplements based on the gut–brain axis.
研究领域:
神经科学
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微生物学
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营养学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Pei Xie,Li-Jun Yan,Hong-Ling Zhou,Hui-Hui Cao,Yuan-Ru Zheng,Zi-Bin Lu,Hua-Yi Yang,Jia-Mei Ma,Yu-Yao Chen,Chuying Huo,Chunyang Tian,Jun-Shan Liu,Lin-Zhong Yu
Background: Acute lung injury (ALI) is a serious inflammatory disease with clinical manifestations of hypoxemia and respiratory failure. Presently, there is no effective treatment of ALI. Although emodin from Rheum palmatum L. exerts anti-ALI properties, the underlying mechanisms have not been fully explored.
Purpose: This study aimed to investigate the therapeutic effect and mechanism of emodin on LPS-induced ALI in mice.
Methods: RAW264.7 cells and zebrafish larvae were stimulated by LPS to establish inflammatory models. The anti-inflammatory effect of emodin was assessed by ELISA, flow cytometric analysis, and survival analysis. In vitro mechanisms were explored by using Western blotting, luciferase assay, electrophoretic mobility shift assay (EMSA), and small interfering RNA (siRNA) approach. The acute lung injury model in mice was established by the intratracheal administration of LPS, and the underlying mechanisms were assessed by detecting changes in histopathological and inflammatory markers and Western blotting in lung tissues.
Results: Emodin inhibited the inflammatory factor production and oxidative stress in RAW264.7 cells, and prolonged the survival of zebrafish larvae after LPS stimulation. Emodin suppressed the expression levels of phosphorylated JNK at Thr183/tyr182 and phosphorylated Nur77 at Ser351 and c-Jun, and increased the expression level of Nur77 in LPS-stimulated RAW264.7 cells, while these regulatory effects of emodin on Nur77/c-Jun were counteracted by JNK activators. The overexpression of JNK dampened the emodin-mediated increase in Nur77 luciferase activity and Nur77 expression. Moreover, the inhibitory effect of emodin on c-Jun can be attenuated by Nur77 siRNA. Furthermore, emodin alleviated LPS-induced ALI in mice through the regulation of the JNK/Nur77/c-Jun pathway.
Conclusions: Emodin protects against LPS-induced ALI through regulation on JNK/Nur77/c-Jun signaling. Our results indicate the potential of emodin in the treatment of ALI.Keywords: acute lung injury, inflammation, lipopolysaccharide, emodin, JNK/Nur77/c-Jun
研究领域:
药理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 3
·
IF 7.7
Chao Li,Han Zhao,Jingjing Wang,Chenfei Liu,Shiqing He,Jingchao Zhou,Liangyu Li,Yiyao Liu,Qingping Wang,Xiaojing Shen,Junjie Wu,Guangquan Chen,Yu Wang,Liang Yang,Bin Du
Tumor-resident microbiota are identified as a critical modulator in the carcinogenesis and progression of cervical malignancies. However, the mechanisms linking these microbiota to cervical cancer remain poorly understood. In this study, we find that patients with cervical cancer exhibit increased microbiota diversity, characterized by eight distinct bacterial species that distinguish them from control subjects. Intratumoral or intravenous administration of an isolated strain, Gordonia polyisoprenivorans GP-2, derived from tumor-resident microbiota, significantly promotes the growth and metastasis of cervical cancer in mice. Further investigation reveals that GP-2 metabolizes host-derived choline to produce the bacterial metabolite lysophosphatidylcholine (lysoPC). We propose and validate the biosynthetic pathway for lysoPC in strain GP-2 and demonstrate that lysoPC activates the classical tumorigenic genes c-Jun / c-Fos using cervical tumor organoids derived from patients. These findings elucidate the mechanisms underlying microbiota-host crosstalk in cervical cancer and highlight a potential therapeutic target for intervening in tumor-resident bacteria.
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高影响因子
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